This invention relates to compositions and methods for enhancing the quality of wound healing. In particular, the invention relates to the healing of corneal wounds. In one embodiment, the invention relates to methods and a composition for improving the results obtainable in keratorefractive surgeries, such as radial keratotomy, by altering the course of healing of the surgical incisions.
A considerable body of literature is devoted to methods for improving wound healing, both in terms of increasing rates of wound healing processes, such as scarring and contraction of healed tissue. Not only are those effects undesirable from a cosmetic point of view, but also, in the case of corneal wounds, they can interfere with visual function.
It is to be understood that the term "wound" as used herein includes surgical incisions as well as wounds caused by accidental trauma.
U.S. Pat. No. 4,444,787 describes the treatment of wounded ocular tissue by the topical application of collagen crosslinking inhibitors to the tissue. Application of the crosslinking inhibitor is said to reduce shrinkage of collagen fibers located in ocular tissue.
U.S. Pat. No. 3,438,378 describes a tissue adhesive comprising a mixture of soluble proteinaceous prepolymer, such as gelatin, a modifying agent in the form of a phenol derivative, and an aldehyde crosslinking agent. The tissue adhesive is applied to the surfaces to be bonded and crosslinking is effected.
A number of publications describe the use of tissue adhesives to bind wound surfaces following accidental corneal perforations or corneal surgery. These include: Ophthalmic Surg., Vol. 15(1), pp. 55-57 (1984); Aust. J. Ophthalmol., Vol. 11(2), pp. 113-118 (1983); Ophthalmology, Vol. 89(6), pp. 630-635 (1982); Ophthalmic Surg., Vol. 13(6), pp. 475-477 (1982); Ophthalmic Surg., Vol. 10(3), pp. 58-64 (1979); J. Biomed. Mater. Res., Vol. 5(1), pp. 113-119 (1971); Trans. Pac. Coast Ophthalmol. Soc., Vol. 50, pp. 121-135 (1969); Trans. Am. Acad. Ophthalmol. Otolaryngol., Vol. 73(3), pp. 499-505 (1969). The most commonly employed adhesives for use in healing wounds of the eye are cyanoacrylate type adhesives.
Most of the foregoing publications describe methods and materials for binding together the surfaces of ocular tissue which has been penetrated accidentally or during surgery. In the cases described, the desired objective is to restore the wounded tissue as nearly as possible to its original configuration. In keratorefractive surgeries, however, incisions are made into the cornea for the specific purpose of permanently changing the geometry of the cornea. Restoration of the tissues to their original configuration, therefore, would tend to reverse the desired effects of the surgery.
Keratorefractive surgeries are intended to correct vision problems caused by defects in the geometry of the eye by surgically altering the corneal geometry. If successful, these techniques offer readily apparent advantages over conventional methods of vision correction, i.e., corrective lenses such as eyeglasses or contact lenses. Corrective lenses are often inconvenient or uncomfortable to wear and are subject to loss or breakage. Contact lenses present a risk of corneal infection and/or abrasion. These problems could be avoided if reliable keratorefractive surgical procedures could be developed that produced predictable, permanent vision correction.
Radial keratotomy is a keratorefractive surgical procedure which is employed to correct myopia caused by excessive corneal curvature. In this technique, a series of incisions is made in the cornea, usually penetrating about 90 to 95% of the thickness of the cornea. The incisions extend along lines which radiate outwardly from the corneal center. The number of incisions may vary from as few as four to as many as 16, with 8 to 12 being commonly employed. The incisions allow the cornea to relax and to flatten out somewhat, thereby reducing or eliminating nearsightedness. Similar procedures, in which corneal incisions are made in directions other than radial directions, have been employed to correct some astigmatisms.
While radial keratotomy and related keratorefractive surgeries have become fairly commonplace, the results achieved using presently available techniques are not highly predictable or controllable in any given patient. In particular, the degree of correction, measured in diopters, is not well controlled and may be more or less than is needed by the particular individual, so that the operation may have to be repeated or corrective lenses may still be needed. Furthermore, the healing process usually takes from 12 to 24 months, during which time some patients experience instability in visual acuity; that is, the cornea begins to reacquire some of the curvature lost as a result of the operation. Maximum flattening of the cornea usually occurs about 2 days after surgery, with a gradual increase in curvature occurring thereafter until the incisions have healed.
Some keratotomy patients have also encountered post-operative vision problems related to scarring. In some instances, scars at the healed incision sites cause light to be reflected within the eye, resulting in a perceived glare, particularly at night. Fluctuations in visual acuity throughout the day may also result.
The aforementioned problems encountered in keratorefractive surgery are related to the manner in which the corneal incisions heal. Yet, no efforts appear to have been made to improve the results obtained in keratorefractive surgery by significantly altering the course of healing of the surgical incisions.
A number of substances have been discussed in the literature in connection with corneal wound healing. Fibronectin, a plasma and extracellular matrix glycoprotein, has been applied as a topical wound-healing agent in the treatment of wounds or defects of the epithelial layer of the cornea (see Phan, T. M. et al., ARVO 1985 Supplement to Investigative Ophthalmology & Visual Science, Vol. 26, No. 3, p. 92 (1985); Nishida et al., Arch. Ophthalmol., 101:1046-1048 (1983); Nishida et al., Ophthalmology, 92, 2, 213-216 (1985)). The appearance of fibronectin at the edges of stromal wounds in rabbit eyes was reported by Suda and coworkers (Current Eye Research, 1, 9, 553-556 (1982)). Dweck and coworkers have reported that type IIIc collagen and fibronectin are deposited at the site of stromal wounds in rabbits (ARVO 1985 Supplement to Investigative Ophthalmology & Visual Science, Vol. 26, No. 3, p. 92 (1985)).